Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial.

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.

Dynamical models of mutated chronic myelogenous leukemia cells for a post-imatinib treatment scenario: Response to dasatinib or nilotinib therapy.

Targeted inhibition of the oncogenic BCR-ABL1 fusion protein using the ABL1 tyrosine kinase inhibitor imatinib has become standard therapy for chronic myelogenous leukemia (CML), with most patients reaching total and durable remission. However, a significant fraction of patients develop resistance, commonly due to mutated ABL1 kinase domains. This motivated development of second-generation drugs with broadened or altered protein kinase selectivity profiles, including dasatinib and nilotinib.

The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia.

The BCR-ABL T315I mutation causes resistance to imatinib, nilotinib and dasatinib in chronic myeloid leukemia. Forty BCR-ABL positive patients with imatinib resistance were analyzed for T315I mutated clones after six months on nilotinib or dasatinib treatment by quantitative allele-specific ligation polymerase chain reaction with a sensitivity of 0.05%.

Circulating monocytes mirror the imbalance in TF and TFPI expression in carotid atherosclerotic plaques with lipid-rich and calcified morphology.

Background: Thrombogenicity of atherosclerotic plaque largely depends on plaque morphology and their content of tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The relationship between morphological composition of plaque (lipid-rich or calcified) and expression of TF and TFPI in circulating blood monocytes and within the plaques is not characterized.

Objective: To investigate whether lipid-rich (echolucent) or calcified (echogenic) morphology of carotid atherosclerotic plaques is associated with differences in TF and TFPI expression in circulating blood monocytes and within carotid atherosclerotic plaques.

BCR-ABL isoforms associated with intrinsic or acquired resistance to imatinib: more heterogeneous than just ABL kinase domain point mutations?

Imatinib, a small molecule inhibitor of ABL, PDGFR and C-KIT, has revolutionized treatment of chronic myeloid leukaemia (CML). However, resistance to treatment is of increasing importance and often is due to point mutations in the Abl kinase domain (Abl KD). Here, we analysed clinical outcome and mutation status in two independent Nordic populations (n = 77) of imatinib-resistant CML patients.

The role of TFPI in regulation of TF-induced thrombogenicity on the surface of human monocytes.

Introduction: Although the procoagulant reactivity of monocytes largely depends on expression and cell surface presentation of tissue factor (TF), little is known about the impact of tissue factor pathway inhibitor (TFPI) on regulation of TF function on the monocyte surface.

Materials And Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy subjects and cryopreserved. We investigated TF and TFPI mRNA expression by reverse transcription-quantitative real-time PCR (RT-qPCR), surface presentation by flow cytometry and confocal microscopy, and TFPI-mediated regulation of TF functional activity on the surface of resting and LPS-stimulated PBMCs by TF activity assay and Calibrated Automated Thrombogram (CAT) assay.

Detection of drug-resistant clones in chronic myelogenous leukemia patients during dasatinib and nilotinib treatment.

Background: Imatinib effectively inhibits the tyrosine kinase activity conferred by the BCR-ABL gene [fusion gene of BCR (breakpoint cluster region) and ABL1 (c-abl oncogene 1, receptor tyrosine kinase)] and thereby appreciably improves outcomes for chronic myelogenous leukemia (CML). A small percentage of patients relapse because of the proliferation of escape clones; such relapses can be treated with second-generation drugs. Early detection and monitoring of resistant clones may provide clinical benefit.

Chronic myelogenous leukemia with the e6a2 BCR-ABL and lacking imatinib response: presentation of two cases.

The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur.

A co-operative evaluation of different methods of detecting BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on second-line dasatinib or nilotinib therapy after failure of imatinib.

Background: Various techniques have been employed to detect BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia who are resistant to imatinib. This has led to different reported frequencies of mutations and the finding of a heterogeneous pattern of individual mutations.

Design And Methods: We compared direct sequencing alone and in combination with denaturing high-performance liquid chromatography and two high-sensitivity allele-specific oligonucleotide polymerase chain reaction approaches for analysis of BCR-ABL mutations in 200 blinded cDNA samples prior to and during second-line dasatinib or nilotinib therapy in patients with chronic myeloid leukemia in whom imatinib treatment had failed.

Intracellular and surface distribution of monocyte tissue factor: application to intersubject variability.

Objective: The high and low responder phenomenon describes individual differences in lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) activity. We characterized patterns of intracellular accumulation, externalization, and shedding of TF in response to LPS in mononuclear cells (MNCs) from high responders (HRs) and low responders (LRs).

Methods And Results: After 2 hours of LPS stimulation of whole blood, flow cytometry analyses revealed a larger population of TF-positive monocytes in HRs (32.